We hypothesize that (1) disruptions of the hypothalamic-pituitary-adrenal (HPA) axis, whether inherent or drug-induced, are central to the development of addictive diseases and in relapse to drug abuse by abstinent former opiate and cocaine addicts, (2) changes of gene expression in the HPA axis and specific brain regions underlie this disruption, and (3) the changes of HPA gene expression and hormonal responses are modulated by both dopaminergic and opioidergic systems. During the last five years, we extended our studies in humans to address changes of HPA gene expression by drugs of abuse using several animal models. The goal of the present proposal for each specific aim is to extend our recent work to study changes in HPA gene expression (quantitative measures of specific mRNA levels) following chronic drug exposure, withdrawal and challenge. We will determine alterations of levels of the following mRNAs: (a) CRF, CRF type I and type II receptors, (b) endogenous opioid system (preprodynorphin, preproenkephalin, proopiornelanocortin and mu, delta, kappa receptors), (c) orphanin FQ and its receptor, and (d) two glucocorticoid receptors, within the HPA axis and specific brain regions (including the hypothalamus, pituitary, amygdala, frontal cortex, hippocampus, and pons/medulla). Most studies will be conducted in Fischer rats, one in Lewis rats, with inherent differences in preference for drugs of abuse, and one in Sprague-Dawley rats. Some studies will be conducted in transgenic mice with engineered disruption of specific HPA related opioid and dopamine genes. The specific aims are to: (1) extend recent studies of acute and chronic intermittent morphine to examine chronic effects of heroin and of early and prolonged withdrawal from chronic heroin with respect to HPA gene expression, hormonal responses, and behavior, (2) extend recent studies of acute, sub-acute or chronic "binge" cocaine to examine the effects of ascending dose chronic "binge" cocaine and to examine early and prolonged withdrawal from chronic "binge" cocaine with respect to HPA gene expression and hormonal responses, (3) extend recent studies of the involvement of dopaminergic and opioidergic systems in changes of HPA gene expression and hormonal responses induced by cocaine or morphine, and (4) study the functional integrity of the HPA axis to specific neuroendocrine stimuli following chronic "binge" cocaine and its withdrawal.